A phase II study of durvalumab re-treatment +/- prednisone in patients who discontinued prior checkpoint therapy due to immune related toxicity (CCTG IND.238A).
Authors: Peter Michael Ellis, Sara Kristina Taylor, Penelope Ann Bradbury, John R. Goffin, Rosalyn A. Juergens, Scott A. Laurie, Geoffrey Liu, Jennifer L. Spratlin, Nicole Grace Chau, Danielle Charpentier, Courtney Coschi, Joana Sederias, Siwei Zhang, Dongsheng Tu, Lesley Seymour, Pierre-Olivier Gaudreau
Journal: Journal of Clinical Oncology (2023)

TPS2673 Background: Up to 18% of patients permanently discontinue immune checkpoint blockade (ICB) therapy following G3/G4 immune-related adverse events (irAEs) even if reversible / easily managed with replacement therapy or steroids. Safety concerns exist with ICB re-treatment. Given the potential benefit of ICB and evidence that patients with irAEs may exhibit greater efficacy, there is interest in ICB rechallenge following successful management of G3/G4 irAEs in patients who have had benefit, and trials to prospectively investigate ways to prevent irAE recurrence are needed. Durvalumab is a human monoclonal antibody of IgG1κ subclass that binds to PD-L1. Canadian Cancer Trials Group (CCTG) IND.238A is a phase 2, open label, multicentre study of durvalumab +/- prednisone rechallenge in patients who were benefitting from prior ICB but discontinued due to irAEs. Methods: Eligible patients have received prior anti-PD-(L)1 ICB alone or in combination with anti-CTLA-4 ICB, with or without chemotherapy/targeted therapy, and experienced either: 1) G3 or selected G4 irAEs (i.e. endocrinopathies manageable with replacement therapy; hematologic toxicity) that required drug discontinuation; 2) prolonged G2 irAEs where therapy was discontinued due to poor tolerability. Prior irAE must have resolved to ≤G1, patients must have completed steroid therapy and have documented RECIST 1.1 CR, PR, or prolonged SD (≥8 weeks) to initial ICB. Patients with prior (neo)adjuvant/consolidation ICB are eligible provided there has been ≥6-month treatment free interval before enrollment. Based on prior irAE, patients are allocated into either: 1) the High Risk cohort, receiving durvalumab (1500mg IV Q4W in all cohorts) + prednisone 0.5mg/kg/day for C1-2, or; 2) the Standard Risk cohort, where they are randomized to receive either durvalumab + prednisone 10mg/day for C1-2 (Cohort 2A) or durvalumab alone (Cohort 2B). Three to 6 patients are enrolled into each cohort initially, then each cohort expands up to a total of 60 evaluable patients (20 per cohort). Safety review takes place following enrollment of the 1 st , 3 rd , 6 th and 10 th patient in each cohort. Safety review occurs 4 weeks after the 1 st patient treated on each cohort and subsequently once the last patient has been followed for at least 4 weeks. The primary endpoint is the incidence of treatment-related AEs (CTCAE v5.0), estimated as percentages of patients with each AE (90% exact CI will be calculated). Secondary objectives are ORR (RECIST 1.1 and iRECIST) and efficacy of corticosteroids in preventing recurrent or new ≥G2 irAEs (90% exact CI will be calculated). Exploratory endpoints include PFS / iPFS by Kaplan-Meier method, exploration of blood- and stool-based irAE biomarkers and PD-L1 expression. As of January 30, 2023, 12 of planned 60 patients have been enrolled. Clinical trial information: NCT03847649 .